Overcoming Anti-PD-1 Resistance in Lung Cancer
Abstract
Objective and rationale: The overall 5-year survival for lung cancer patients remains dismally low, despite advances in traditional treatment options such as surgery, chemotherapy, and radiation. Immune-based therapies represent a new treatment modality. After many years of promise and disappointment, one specific approach, i.e., immune checkpoint blockade, has recently shown impressive therapeutic activity in the clinic. This approach utilizes reagents, called antibodies, that can restore tumor-killing function to specific immune cells, called cytotoxic T-cells, by blocking physiological regulatory mechanisms that suppress T-cells (essentially “taking the brakes off”). Specifically, two antibodies (Pembrolizumab and Nivolumab) that target the same regulatory molecule on T-cells have been approved by the Food and Drug Administration (FDA) for use in previously treated non-small-cell lung cancer patients, based on an 18-29% overall response rate in patients that fail conventional therapy. More recently, Pembrolizumab was approved as a first-line treatment, based on an overall response rate of 44.8% vs. 27.8% achieved with standard chemotherapy. Whereas these results represent a new paradigm and hope for lung cancer patients, a significant proportion still do not respond to immune therapy. The reasons for this are not fully understood, and most studies are now focused on delineation of the factors that drive resistance to immune therapy. We have found in a mouse model of spontaneous lung cancer that resistance to immune checkpoint blockade may be due to an unanticipated activity of the therapeutic antibody itself. Our studies reveal that lung tumors contain different types of T-cells and that the therapeutic antibodies can react with different types of T-cells, i.e., both beneficial antitumor T-cells, but also with T-cells that produce molecules that can promote tumor growth (in this case Interleukin-17). Indeed, when the therapeutic antibody is administered along with reagents that neutralize Interleukin-17 (i.e., an anti-Interleukin-17 antibody), treatment worked and tumors were eliminated. This is a completely new finding. Importantly, studies have shown that both such antitumor and pro-tumorigenic T-cells exist in human tumors, establishing human relevance. The goals of our proposal are twofold. First, we will dissect the mechanisms that underlie the dual activity of the therapeutic antibody and determine how the harmful molecules (Interleukin-17) produced by one T-cell subset interfere with the antitumor activity of the other (cytotoxic T-cell). The second objective is to understand the origin of the “harmful” T-cell subset in the cancerous lung, which we hypothesize is tied to the specific types of microbes that occupy the lung. If we find that this is true, one can then not only predict the ability of a patient to respond to immune therapy by determining the microbial composition of the lung, but it could lead to the development of strategies that are designed to proactively modulate lung microbe composition to reduce cancer risk. Areas of Emphasis: Our proposal is consistent with three areas of emphasis: (1) Identify innovative strategies for prevention and treatment of lung cancer; (2) Understand predictive markers to identify responders and non-responders; and (3) Understand mechanisms of resistance to treatment. Ultimate applicability of the research: This proposal will ultimately help those patients that have failed both conventional and immune therapy by introducing a completely new treatment approach. Importantly, the proposed concept is highly translational in nature and can be tested in the clinic very rapidly, as both immune checkpoint blockade antibodies and anti-Interleukin-17 antibodies have already been approved by the FDA for use in different diseases. If our studies provide convincing proof-of-principle, it may take less than a year to evaluate the basic notion in patients t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910265
Entities
People
- Nejat K Egilmez
Organizations
- United States Army
- University of Louisville